ABSTRACT
Cell fate decisions are driven by lineage-restricted transcription factors but how they are regulated is incompletely understood. The C/EBPα-induced B cell to macrophage transdifferentiation (BMT) is a powerful system to address this question. Here we describe that C/EBPα with a single arginine mutation (C/EBPαR35A) induces a dramatically accelerated BMT in mouse and human cells. Changes in the expression of lineage-restricted genes occur as early as within 1 hour compared to 18 hours with the wild type. Mechanistically C/EBPαR35A exhibits an increased affinity for PU.1, a bi-lineage transcription factor required for C/EBPα-induced BMT. The complex induces more rapid chromatin accessibility changes and an enhanced relocation (‘stealing’) of PU.1 from B cell to myeloid gene regulatory elements. Arginine 35 is methylated by Carm1 and inhibition of the enzyme accelerates BMT, as seen with the mutant. Our data suggest that the relative proportions of methylated and unmethylated C/EBPα in bipotent progenitors determine the velocity of cell fate choice and also affect lineage directionality. This could represent a more general mechanism that coordinates the speed and faithfulness of cell fate conversions.
Competing Interest Statement
The authors have declared no competing interest.
